The liver is the second largest organ in the body. Anatomically, the liver is located in the abdominal cavity below the right diaphragm with the gallbladder and duodenum below and the stomach flanked to the left. See FIG. 1 for an illustration of its anatomical relationship to other organs in the abdomen. The liver's blood supply system is unique. It has a dual blood supply system—blood is supplied via both the hepatic artery and the portal vein. The liver is the first organ to receive a nutrient-enriched blood supply from the digestive tract's portal circulation. Its unique vascular architecture provides unparalleled access to nutrients and xenobiotics absorbed through the digestive tract.
The liver plays critical roles in a myriad of metabolic pathways and synthetic functions of the body. Processing and redistribution of metabolic fuels such as glucose and fatty acids are major responsibilities of the liver. Diverse biochemical pathways in the liver modify and detoxify compounds absorbed from the intestine. The liver is the major synthetic site for serum proteins involved in coagulation, transport proteins such as albumin, iron binding proteins, and protease inhibitors: The liver is also the major site for synthesis of acute-phase reactants, a diverse group of proteins that are expressed during acute and chronic systemic inflammation. The functions of these proteins include roles in host defense against tissue damage and infection.
The liver also possesses the unique capacity to undergo rapid regeneration and replacement of damaged of dead cells within itself (Stolz, D. B. and G. K. Michalopoulos (1998), “Differential modulation of hepatocyte growth factor-stimulated motility by transforming growth factor betal on rat liver epithelial cells in vitro.” J Cell Physiol 175(1): 30-40).
Diseases of the liver affect millions of people worldwide and kill tens of thousands on a daily basis. The largest groups of liver disease are liver cancer, cirrhosis, and hepatitis of the liver. The pathophysiology of these diseases are well studied, but treatment options remain poor and there are currently no definitive cures.
Cancers of the Liver
Cancers of the liver can be divided into two major categories; primary and metastatic. Primary liver cancers arise from within the liver itself, from hepatocytes (hepatocellular carcinoma), bile duct epithelium (hepatobiliary carcinoma), or mesenchymal tissue (angiosarcoma). Metastatic liver cancers arise from distant sources and secondarily spread to the liver through either the blood stream (hematogenous metastasis) or rarely through direct extension from a neighboring organ. Of the primary liver cancers, the most common is hepatocellular carcinoma (Kew, M. C. (1998). “Hepatitis viruses and hepatocellulai carcinoma.” Res Virol 149(5): 257-62).
Hepatocellular cancer arises from the epithelial cells of the liver called hepatocytes. Malignant changes in heptocytes cause uncontrolled proliferation of monoclonal or polyclonal cells that result in nodular, massive or diffuse pathologic varieties of hepatocellular cancer. Eventually, proliferation of the tumor results in functional compromise of the liver and metastatic spread to lungs and other organs. Death is usually from a combination of liver failure and disseminated cancer-induced multi-organ failure (Aguayo, A. and Y. Z. Patt (2001). “Liver cancer.” Clin Liver Dis 5(2): 479-507).
Hepatocellular carcinoma is the seventh most common cancer in men and ninth in women, causing between 310,000 to 1 million new cases each year (Aguayo and Patt 30 2001). Hepatocellular cancer is the world's most common, solid-organ malignancy and is responsible for over 1 million deaths annually (Aguayo and Patt 2001). Men are generally more susceptible than women to hepatocellular carcinoma. Male predominance is more obvious in populations at high risk (mean ratio 3.7:1) (Kew 1998). The incidence of hepatocellular carcinoma generally rises progressively with age, although it tends to level off in the oldest age groups. Diagnosis usually occurs between 50-70 years (Kew 1998). There is a geographic predilection of hepatocellular cancer in East Asia and Sub-Saharan Africa (Kew 1998). In high-risk areas such as Southeast Asia, China, Japan, and sub-Saharan Africa the prevalence is greater than 100 per 100,000 population. In the U.S., there are 20,000 new cases of liver cancer diagnosed per year and over 15,000 attributed deaths per year (Aguayo and Patt 2001).
Hepatocarcinogenesis is a complex incremental process that usually evolves over many years (see FIG. 2). Four major (and several minor) causal associations of the tumor have been identified. These vary in importance based on prevalence of risk factors in different geographic locations. The four major factors include 1) chronic hepatitis-B infection, 2) chronic hepatitis-C infection, 3) exposure to aflatoxin and 4) cirrhosis of the liver. Minor factors that have been linked to the incidence of liver cancer include oral contraceptives, cigarette smoking, and a variety of inherited metabolic disorders and membranous obstruction of inferior vena cava (Kew 1998).
Hepatitis of the Liver
Hepatitis is an inflammation of the liver that causes liver damage and dysfunction. Hepatitis can result from a viral infection or from a variety of non-viral etiologies. However, the most common cause of hepatitis is from viral infections. Of the many viruses that cause hepatitis, Hepatitis B and C viruses are the two most common causes of hepatitis and the most strongly associated with development of hepatocellular cancer Moradpour, D., A. Cerny, et al. (2001). “Hepatitis C: an update.” Swiss Med Wkly 131(21-22): 291-8; Moradpour, D., B. Wolk, et al (2001). “Hepatitis C: a concise review.” Minerva Med 92(5): 329-39). Although infection with either of these viruses can cause severe, acute liver damage and resultant fulminant hepatic failure and death, most cases result in chronic inflammation. Chronic inflammation is manifested by moderate elevations in the hepatic enzymes Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), which are markers of ongoing hepatocellular injury and hepatocyte death. Approximately 80% of hepatocellular cancers are associated with chronic hepatitis-B infection (Kew. 1998).
Furthermore, as many as 50% of patients with chronic hepatitis-B infection will go on to develop cirrhosis and hepatocellular cancer. Chronic hepatitis-C infection is similarly implicated in development of hepatocellular cancer with some studies showing 83% of patients with this cancer have chronic infection. It is unclear if the two viruses act synergistically to promote carcinogenesis (Moradpour, Cemy et al. 2001; Moradpour, Wolk et al. 2001). In the U.S. there are 4 million people with chronic viral hepatitis and the number is growing. In Asia, some countries, including Japan and Taiwan, have an even higher prevalence of chronic hepatitis infection (Kew 1998).
Alcohol abuse can also cause acute and chronic hepatitis. Alcoholic hepatitis can range from a mild hepatitis, with abnormal laboratory tests being the only indication of disease, to severe liver dysfunction with complications such as jaundice (yellow skin caused by bilirubin retention), hepatic encephalopathy (neurological dysfunction caused by liver failure), ascites (fluid accumulation in the abdomen), bleeding esophageal varices (varicose veins in the esophagus), abnormal blood clotting and coma. Histologically, alcoholic hepatitis has a characteristic appearance with ballooning degeneration of hepatocytes, inflammation with neutrophils and sometimes Mallory bodies (abnormal aggregations of cellular intermediate filament proteins). Alcoholic hepatitis is reversible if the patient stops drinking, but it usually takes several months to resolve. Alcoholic hepatitis can lead to liver scarring and cirrhosis. Chronic alcoholism is the most common cause of cirrhosis in the U.S.; thirteen million Americans suffer from chronic alcoholism and 10-20% of these patients eventually develop liver cirrhosis (Naccarato, R. and F. Farinati (1991)). “Hepatocellular carcinoma, alcohol, and cirrhosis: facts and hypotheses.” (Dig Dis Sci, 36(8):1137-42). Although the incidence of liver cancer from alcoholic cirrhosis is lower than from hepatitis cirrhosis, there is a strong association that exist and there are many more people with alcoholic cirrhosis than hepatitis cirrhosis (Seitz, H. K., G. Poschl, and U. A. Simanowski (1998). “Alcohol and Cancer.” Recent Dev. Alcohol 14:67-95; Naccarato et al. 1991).
Exposure to Chemicals and Toxins
Exposure to certain chemicals and toxins can lead to hepatocellular carcinoma. Perhaps the best known and most extensively studied of these is aflatoxin. Aflatoxin is a poison produced by the mould Aspergillus Flavus. Aflatoxin can contaminate stored foods such as peanuts, grains and cassava, especially in tropical areas. Dietary contamination with aflatoxin has been a particular problem in some underdeveloped countries in Africa and Far East Asia. Aflatoxin readily causes liver cancer in laboratory animals and, in man, may potentiate the cancer-causing effects of hepatitis B infection (Ross, R. K., J. M. Yuan, et al. (1992)). “Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma.” (Lancet 339(8799):943-6). However, the extent of its role as a cause of hepatocellular carcinoma in S humans is not yet fully understood.
Cirrhosis of the Liver
It is believed that chronic liver damage that leads to cirrhosis also predisposes normal hepatocytes to undergo malignant change. Cirrhosis is characterized anatomically by widespread nodules in the liver combined with fibrosis. Cirrhosis of the liver can be defined as the widespread scaring of the liver tissue that, despite the regenerative potential of hepatocytes, results in structural and functional compromise of the liver. Cirrhosis is the end product of a wide variety of liver disorders. In the United States, alcohol abuse is the leading cause of liver cirrhosis. Cirrhosis can result from many causes other than alcohol such as chronic viral hepatitis, metabolic and biliary diseases. The co-existence of another chronic liver disease in a patient who abuses alcohol likely increases the risk of developing cirrhosis (e.g. an alcoholic with chronic viral hepatitis C). Some of the complications of cirrhosis are jaundice, ascites, edema, bleeding esophageal varices, blood coagulation abnormalities, coma and death.
Although, the question of whether alcohol, by itself, causes heptocellular carcinoma has not been fully resolved, it is known that cirrhosis can lead to end-stage liver disease like liver cancer, which often arises in the presence of alcohol cirrhosis. It is not known whether the underlying cirrhosis or the alcohol itself predisposes one to cancer. Alcohol use can increase the risk of hepatocellular carcinoma due to hepatitis B virus, but a similar role in hepatitis C virus-associated hepatocellular carcinoma has not been observed (Shimizu S., K. Kiyosawa, et al. (1992). “High prevalence of antibody to hepaptitis C virus in heavy drinkers with chronic liver diseases in Japan.” J Gastroenterol Henatol 7(1):30-5). The role of cirrhosis in hepatocellular carcinogenesis appears to be that of a promoter (Giovannini, M., D. Elias, et al. (2001). “Hepatocellular carcinoma.” Br J Cancer 84 Suppl 2: 74-7). Whether hepatocellular carcinoma is ever an inevitable consequence of cirrhosis per se is uncertain. Chronic hepatitis B or C infection, alcohol abuse, or both can result in cirrhosis, which regardless of etiology can be complicated by tumor formation. Studies have shown that cirrhotic patients have a 5 to 10% annual risk of developing liver cancer (Aguayo and Patt 2001).
Treatments for Diseases of the Liver
The most common diseases of the liver include hepatitis from alcohol, viral, 5 metastatic and autoimmune etiology, cirrhosis and cancer of the liver. At present time, treatment options are very limited in all cases.
Even with the many advances in medicine and increasing number of treatment options for liver cancer, the prognosis remains poor, and life expectancy remains dismal. Symptomatic hepatocellular carcinoma carries a grave prognosis, largely because of the extent of tumor burden when the diagnosis is made and the presence of coexisting cirrhosis so much so that the annual mortality rate from the tumor is virtually the same as the annual incidence. From the time of diagnosis, the average life expectancy is less then 1 year, with the majority of people dying within 3 to 6 months (Aguayo and Patt 2001).
Therapeutic options for primary liver cancer can be considered depending on the stage of the hepatocellular cancer, which correlate to three distinct developmental stages of the disease. The first stage occurs prior to the actual diagnosis of cancer. Such first stage therapeutic options are presented to patients having major risk factors. These therapies are generally labeled chemoprevention. The second stage is relevant for patients initially diagnosed with a solitary liver mass with dimensions amenable to resection or transplantation and no evidence of distant disease. These strategies may be considered as potentially curative. The therapeutic options associated with the final stage of the disease arise upon instances where either the primary mass is unresectable, because of its size or location, and/or there is extensive distant disease. Strategies at this stage are confined to palliation.
Chemoprevention Therapy of Liver Cancer
Chemoprevention is the concept of interfering with the metabolism of a carcinogen, preventing it from interacting with nucleophiles (especially DNA), and/or preventing precancerous lesions from progressing to cancer (Okuno, M., S. Kojima, et al. (2001). “Chemoprevention of hepatocellular carcinoma: concept, progress and perspectives.” J Gastroenterol Hepatol 16(12): 1329-35). Since the major risk factor for liver cancer has been hepatitis induced cirrhosis, much of the chemopreventative efforts have centered on preventing and treating hepatitis infection. Hepatitis B vaccination has had a tremendous impact on infection rate of Hepatitis B in Asia and the U.S. For patients already infected with hepatitis, the only treatment modality that has shown potential benefit in preventing or slowing the development of cirrhosis and liver cancer is interferon injection. Interferon is an anti-viral agent, which has been shown to lower viral load and decrease the amount of liver damage. Progression of chronic hepatitis is followed by measuring viral load (amount of virus in the body) and the amount of liver damage which can be measured by the elevation of liver enzymes—AST and ALT in the blood. The response rate for interferon therapy of chronic hepatitis varies. The overall response rate is roughly 50% (response defined by normalization of liver enzyme levels and reduction of viral load) (Okuno, Kojima et al. 2001). However, approximately half of the responders will have resumption of elevated liver enzymes and viral load once they stop the injections (Okuno, Kojima et al. 2001). The side effects of interferon are severe and can include general malaise, flu-like symptoms, and moderate to severe anemia. Thus, prolonged treatment with interferon is difficult, especially for older patients or others with comorbid conditions. Even healthy individuals find it difficult to maintain prolonged therapy because of the side effects adversely affecting their daily activities (Okuno, Kojima et al. (2001)).
Curative Therapies for Liver Cancer
The only treatment modalities considered as curative are surgical resection of the liver mass and liver transplantation. (Kuyvenhoven, J., C. B. Lamers, et al. (2001). “Practical management of hepatocellular carcinoma.” Scand J Gastroenterol Suppl 234: 82-7). However, less than 15% of patients with liver cancer are candidates for curative therapy upon diagnosis. Considering that the best survival rates are less than 70% at 5 years with up to 70% recurrence after surgery, curative therapy is really a misnomer (Georgiades, C. S., D. E. Ramsey, et al. (2001). “New nonsurgical therapies in the treatment of hepatocellular carcinoma.” Tech Vasc Intern Radiol 4(3): 193-9; Giovannini, M., D. Elias, et al. (2001). “Hepatocellular carcinoma.” Br J Cancer 84 Suppl 2: 74-7).
The mainstay of the curative strategies is partial hepatectomy (removal of part of the liver that houses the tumor). Over the past decade improvement in peri-operative management has resulted in the procedure related mortality of less then 10%, but the actual number varies from institution to institution. Patients with underlying liver cirrhosis have a higher peri-operative mortality rate, as high as 15% (Kuyvenhoven, Lamers et al. 2001). The regenerative capacity of the liver allows for up to two thirds of the liver mass to be resected in patients without preexisting cirrhosis. Again, surgical resection is hampered because the majority of patients with hepatocellular cancer have underlying cirrhosis. Cirrhotic livers present particular challenges to the surgeon, including, difficult surgical dissection, predisposition to excessive bleeding and postoperative liver failure secondary to compromised reserves. Other exclusionary criteria for surgery include a cancer larger than 5 cm, involving both lobes of the liver, straddling the portal vein, and having distant metastatic deposits. The 5-year survival after partial hepatectomy is 30% to 50%. This compares favorably with the dismal 5% survival with non-surgical therapy, but remains an insufficient cure, since greater then half of these patients die within 5 years (Kuyvenhoven, Lamers et al. (2001)). Despite the potential for cure, 80% of partial hepatectomy survivors develop disease recurrence. Despite technical advancement and improved mortality rates, the fact remains that, even after resection, persons diagnosed with primary liver cancer do not have a hopeful prognosis (Kuyvenhoven, Lamers et al. (2001)).
Theoretically, total hepatectomy with orthotopic liver transplantation (OLT) is the optimum treatment for liver cancer. It provides removal of the primary tumor and the cirrhotic hepatic parenchyma, both of which increase life expectancy. Removing the diseased liver also prevents local recurrence from microscopic tumor disease that may have initiated elsewhere in the liver, distant from the initial tumor. This fact is confirmed through 5 year survival rates of 50-60% after transplantation (Kashef, E. and J. P. Roberts (2001)). “Transplantation for hepatocellular carcinoma.” Semin Oncol 28(5): 497-502). Due to the very limited number of organ donors available, strict transplant criteria have been established. This ensures that the limited number of donated livers go to the best, most suited host. The average wait period for a liver transplantation is between 6 months to 2 years (Kashef and Roberts (2001)). Many patients die while they are on the wait list or are dropped from the list secondary to tumor growth or spread to other organs. Even after transplantation, tissue rejection and life-long immunosuppressant complicates quality of life and longevity. Living related donors reduce the chances of rejection, however, at a prohibitive cost to the donor. (Kashef and Roberts (2001)).
Palliative Procedures for Liver Cancer
The majority of patients with liver cancers are diagnosed at a stage at which the preventive and curative measures are no longer effective treatment options. Therefore, significant development and research have focused on palliative options. Patients who are not candidates for surgical resection or transplantation can be considered for a variety of minimally invasive procedures that appear to provide mediocre improvement in survival. Such procedures include alcohol, cryogenic or radio-frequency ablation, and chemotherapeutic embolization. Although significant strides have been made for chemotherapeutic regiments for other types of cancer in the last 20 years, these treatments have not made a significant impact on the survival rate among liver cancer patients. It may be stated that the quality of life for patients with unresectable liver cancer rapidly deteriorates. Non-traditional therapies such as vitamins and herbal remedies constitute the remaining balance of therapeutic options. However, these therapies have yet to have a significant impact on survival or proven therapeutic benefit to the patient.
Ablative therapies were developed to shrink tumor mass to improve surgical resectability or as bridging procedure while patients await transplantation. Such procedures include percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization.
Percutaneous ethanol injection (PEI) has been the mainstay of palliative therapy for small or multiple unresectable liver cancers for over two decades. Percutaneous radiology-guided injections of purified ethanol are made into a distinct tumor mass. Ethanol induces tumor cell death through cellular dehydration, microvascular thrombosis, and coagulation necrosis (Barnett, C. C., Jr. and S. A. Curley (2001). “Ablative techniques for hepatocellular carcinoma.” Semin Onco 128(5): 487-96). However, utilization of PEI is limited in that it cannot be administered to patients having poor hepatic function, lesions larger than 3 cm or more than 3 lesions (Barnett and Curley 2001). Overall, long term survival remains unaffected
Radiofrequency (RF) ablation and cryoablation (CA) are two methods that induce tumor cell death by extreme heat and cold, respectively. RF is accomplished by introducing a probe into the tumor and heating the tumor to a specific temperature, using radiofrequency emissions. CA also employs a probe that causes freezing induced tumor necrosis directly as well as through microvascular thrombosis directly to the tumor site. Again, the primary use for these therapies is as bridging modalities while patients await curative surgery. (Little, S. A. and Y. Fong (2001). “Hepatocellular carcinoma: current surgical management.” Semin Oncol 28(5): 474-86) and (Barnett and Curley (2001)). The observed benefit in survival is marginal at best when used alone.
Transarterial chemoembolization (TACE) is performed by fluoroscopically cannulating the major hepatic artery and injecting chemotherapeutic and embolizing agents directly into the vascular territory of the tumor. The preferred result is tumor-targeted chemotherapy and ischemia with resultant tumor necrosis. As with other ablative therapies, the major utility of TACE lies in bridging patient treatment while surgical therapy is awaited. No significant long-term improvement in survival has been noted. (Little and Fong 2001) (Barnett and Curley 2001).
Although the ablative therapies have been shown to shrink the liver tumor in many cases and has been used effectively as bridging therapy for patients awaiting definitive therapy, the use of these ablative techniques alone has not been proven to provide either cure or increased survival for patients with hepatocellular carcinoma. These are all invasive procedures and, accordingly, all have risks associated with anesthesia and general surgical complications such as bleeding and infection. There is also the inherent risk of fulminent liver failure if too large of an area of the liver is ablated. Therefore, these therapies come with significant risk, high costs, and without appreciable long-term benefit.
Despite impressive improvement in survival and many cures with systemic chemotherapy for cancers in general, results of chemotherapies in liver cancer are dismal. Doxorubicin, the only FDA approved agent for liver cancer is effective in less than 20% of patients. However, the median survival rate remains less than 6 months (Leung, T. W. and P. J. Johnson (2001). “Systemic therapy for hepatocellular carcinoma.” Semin Oncol 28(5): 514-20). The latest phase III clinical trial showed that the response rate of Doxorubicin to be only 11% with median survival of patients treated with Doxorubicin to be 7 months. Clinical trials are ongoing with many agents either as mono-therapy or poly-therapy including cisplatin, 5-fluorouracil, mitomycin C, gemcitabine and interferon, as well as many others, There is no definitive data to establish any of these trial agents as a standard of care. Although, their efficacy remains to be established, all of these agents have well established significant undesired and deleterious side-effect without an improvement in survival (Leung and Johnson 2001; Treiber, G. (2001). “Systemic treatment of hepatocellular carcinoma.” Dig Dis 19(4): 311-23).
Induction of apoptosis, or programmed cell death, in liver cancer cell cultures has prompted investigation of therapeutic effects of Vitamin A (retinoic acid) in patients with liver cancer (Muto, Y., H. Moriwaki, et al. (1996). “Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group.” N Engl J Med 334(24): 1561-7.; Nakamura, N., Y. Shidoji, et al. (1996). “Apoptosis in human hepatoma cell line induced by 4,5-didehydro geranylgeranoic acid (acyclic retinoid) via down-regulation of transforming growth factor-alpha.” Biochem Biophys Res Commun 219(1): 100-4). Retinoic acid can exist in multiple, sometimes interchangeable isomeric states (i.e. cis and trans). Clinical studies with beta-all trans retinoic acid failed to demonstrate any benefit despite promising experimental data (Meyskens, F. L., Jr., J. Jacobson, et al. (1998). “Phase II trial of oral beta-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157).” Invest New Drugs 16(2): 171-3). Other forms of retinoic acid are being investigated in clinical studies.
Other vitamins are being investigated for their potential therapeutic effects. For example, Vitamin E supplements have been shown to reduce liver damage in patients with chronic Hepatitis B. In a study in rats, Vitamin C and Vitamin K have been shown to have synergistic apoptosis-inducing actions in hepatocellular carcinoma in rats (Sakagami, H., K. Satoh, et al. (2000). “Apopttisis-inducing activity of vitamin C and vitamin K” Cell Mol Biol (Noisy-le-grand) 46(1): 129-43). Vitamin C and Aloe Vera supplements have been shown to reduce the severity of chemical hepatocarcinogenesis (Shamaan, N. A., K. A. Kadir, et al. (1998). “Vitamin C and aloe vera supplementation protects from chemical hepatocarcinogenesis in the rat.” Nutrition 14(11-12): 846-52).
Herbal remedies have been investigated as starting points in an attempt to extract possible biologically active agents for myriad pharmacotherapies. Cancer therapy is no exception, with many current products used to combat cancer originally derived from various herbs and plants. Currently, there are countless claims of herbal products with anti-cancer effects. However, only the few that have had published anti-cancer data will be discussed. Indeed, the research involving “natural” remedies discussed herein, has involved primarily animal models and cell lines. In the few studies performed in humans, none present imaging, laboratory data, or other evidence to support their claims. Moreover, there are no conclusive studies for any of these products.
The herbal medicine “Sho-saiko-to” (TJ9) (a mixture of 7 herbs: bupleurum root, pinellia tuber, scutellaria root, jujube fruit, ginseng roots, glycyrrhiza root, and ginger rhizome) has been reported to inhibit liver cancer development (hepatocarcinogenesis) and proliferation in certain liver cancer cell lines and in rat models (Sakaida, I., Y. Matsumura, et al. (1998). “Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.” J Hepatol 28(2): 298-306).
Paeoniae Radix (PR) is the root of the traditional Chinese Herb called Paenoniae lactiflora Pallas, which has been commonly used to treat liver cancer in China for centuries. Several early studies have shown that extracts of PR have some anticancer growth activities. One study has shown that there is evidence that PR extract can induce programmed cell death (apoptosis) in two human hepatoma cells lines (Lee, S. M., M. L. Li, et al. (2002). “Paeoniae Radix, a Chinese herbal extract, inhibit hepatoma cells growth by inducing apoptosis in a p53 independent pathway.” Life Sci 71(19): 2267-77).
Lemon grass (Cymbopogon citrates, Stapf) in extracts have been shown to inhibit hepatocarcinogenesis in rats. Therefore, it is implicated as a possible chemopreventive agent (Puatanachokchai, R., H. Kishida, et al. (2002) “Inhibitory effects of lemon grass (Cymbopogon citratus, Stapf) extract on the early phase of hepatocarcinogenesis after initiation with diethyInitrosamine in male Fischer 344 rats.” Cancer Lett 183(1): 9-15).
Aloe-emodin is a compound present in traditional medicinal plants like Rhei Rhizoma and Aloe Vera. Several studies have shown that aloe-emodin may induce two separate apoptotic pathways in two human hepatoma cells lines. It is being investigated as a possible chemopieventative agent (Lee, K. Y., J. H. Park, et al. (1997). “Aloesin up-regulates cyclin E/CDK2 kinase activity via inducing the protein levels of cyclin E, CDK2, and CDC25A in SK-HEP-1 cells.” Biochemistry & Molecular Biology International 41(2): 285-92; Corsi, M. M., A. A. Bertelli, at al. (1998). “The therapeutic potential of Aloe Vera in tumor-bearing rats.” International Journal of Tissue Reactions 20(4): 115-8; Kuo, P. L., T. C. Lin, et al. (2002). “The antiproliferative activity of aloe-emodin is through p53-dependent and p21-dependent apoptotic pathway in human hepatoma cell lines.” Life Sciences 71(16): 1879-92).
The herbal/Japanese medicine SNMC (Stronger Neo-Minophagen C), whose active component is glycyrrhizin (a saponin extracted from licorice) has been utilized to improve the liver function in China and Japan. Preliminary data suggest it is effective in helping to prevent hepatocarcinogenesis in patients with Hep B/C with cirrhosis (Arase, Y., K. Ikeda, et al. (1997). “The long term efficacy of glycyrrhizin in chronic hepatitis C patients.” Cancer 79(8): 1494-500).
One study reports that pu tuo ointment and herbs when applied as an ointment and taken orally can improve survival in patients with primary liver cancer (Wang, D. L. (1990). “[Analysis of 70 cases of primary liver carcinoma treated by pu tuo ointment and herbs].” Zhong Xi Yi Jie He Za Zhi 10(12): 723-5, 708).
AHCC (Active Hexose Correlated Compound), an extract obtained from several kinds of basidiomycetes (Chinese mushrooms) has been shown to improve survival and reduce recurrence in patient after resection of hepatocellular carcinoma (Thane, U., S. Bagadey, et al. (2000). “Modulation of programmed cell death by medicinal plants.” Cell Mol Biol (Noisy-le-grand) 46(1): 199-214).
Dietary carotenoid-rich extracts from carrots, tomatoes, and orange juice have been shown in rat models to substantially inhibit biochemical and cellular events thought to play a role in early stages of hepatocarcinogenesis (He, Y., M. M. Root, et al. (1997). “Effects of carotenoid-rich food extracts on the development of preneoplastic lesions in rat liver and on in vivo and in vitro antioxidant status.” Nut Cancer 27(3): 238-44).
Epidemiological studies give evidence that cruciferous vegetables (CF), including broccoli and broccoli extracts, protect humans against cancer. Results from animal experiments show a reduction in chemically induced tumor formation (Zhang, Y., P. Talalay, et al. (1992). “A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure.” Proc Natl Acad Sci USA 89(6): 2399-403)